The objectives of this proposed research are (a) to establish the relationship of mitochondrial monovalent ion uptake and extrusion to the physiological roles of K plus and Na plus in the heart, (b) to examine the mechanism of mitochondrial cation uptake and its relationship to oxidative phosphorylation, and (c) to determine how ion uptake and extrusion effects mitochondrial volume control (swelling and shrinking), both in isolated mitochondria and in the mitochondria of the intact heart. Energy-linked and passive movements of Na plus and K plus into and out of isolated heart mitochondria will be followed by direct analysis, isotope distribution, and osmotic swelling and contraction. The conditions which favor electrogenic ion penetration and those which require a carrier-mediated exchange will be defined and related to the mitochondrial energy-coupling process. The properties of mitochondrial ion uptake and extrusion reactions, especially those which result in osmotic swelling and contraction, will be examined in media chosen to mimic the intracellular milieu. The factors which control the normal flow of cations and anions into and out of the mitochondrion under these conditions will be defined. A number of membrane alterations which affect the rate and extent of mitochondrial ion uptake, and hence affect the volume of the mitochondrion, have been defined. The effect on mitochondrial ion movements and volume changes of a number of such agents and conditions which may arise during ischemia will be examined. The proposed studies will explore the relationship between cellular events which lead to irreversible cell injury following ischemia (and a number of other pathological changes) and alterations in the structure and function of heart mitochondria. A definition of the exact sequence of events which leads to mitochondrial swelling and deterioration when heart tissue becomes ischemic will be sought. BIBLIOGRAPHIC REFERENCES: Altschuld, R.A., Merola, A.J., and Brierley, G.P., The Permeability of Heart Mitochondria to Creatine, J. Molecular Cellular Cardiology, 7, 451-462, (1975). Brierley, G.P., The Uptake and Extrusion of Monovalent Cations by Heart Mitochondria: Molecular and Cellular Biochemistry, 10, 41-62 (1976).